Inflammation disorders, such as arthritis, colitis, and autoimmune diabetes typically manifest themselves as disorders distinct form those associated with reperfusion injury, e.g., stroke and heart attack, and can present clinically as different entities. However, there can be common underlying mechanisms between these two types of disorders. In particular, inflammation and reperfusion injury can induce proinflammatory cytokine and chemokine synthesis. Induction of pro-inflammatory cytokines can, in turn, result in production of cytotoxic free radicals such as nitric oxide (NO) and superoxide. Nitric oxide and superoxide can react to form peroxynitrite (ONOO−). Szabó et al., Shock 6:79-88, 1996.
Peroxynitrite-induced cell necrosis observed in inflammation and reperfusion injury involves, in significant part, the activation of the nuclear enzyme poly (ADP-ribose) synthetase (PARS). Activation of PARS is thought to be an important step in the cell-mediated death observed in inflammation and reperfusion injury. Szabó et al., Trends Pharmacol. Sci. 19: 287-98, 1998.
A number of PARS inhibitors have been described in the art. See, e.g., Banasik et al., J. Biol. Chem., 267:1569-75, 1992, and Banasik et al., Mol. Cell. Biochem., 138:185-97, 1994. Additionally, some potent PARS inhibitors are reported in, for example, WO 00/39104, WO 00/39070, WO 99/59975, WO 99/5973, WO 99/11649, WO 99/11645, WO 99/11644, WO 99/11628, WO 99/11628, WO 99/11623, WO 99/11311, WO 00/42040; Zhang et al, Biochem. Biophys. Res. Commun., 278:590-98, 2000, White et al., J. Med. Chem., 43:4084-4097, 2000; Griffin et al., J. Med. Chem., 41:5247-5256, 1998; Shinkwin et al., Bioorg. Med. Chem., 7:297-308, 1999. Furthermore, side effects of some of the best known-PARP inhibitors have been discussed in Milan et al, Science, 223:589-591, 1984.
Certain isolindolinone derivatives are known in the art. For example, inhibitors of platelet aggregation are reported in Egbertson et al., J. Med. Chem., 42:2409-21, 1999; dopamine D4 receptor isoindolinones are reported in Belliotti et al., Bioorg. Med. Chem. Lett., 8:1499-502, 1998; antipsychotic agents are disclosed in Norman et al., J. Med. Chem., 37: 2552-63, 1994 and in Normal et al., J. Med. Chem., 36: 3417-23, 1993. The antiarrhythmic activity of isoindolione is shown in Dugger et al. Drug Metab. Dispos. 4:262-268, 1976, and substituted 2,3-dihydro-1H-isoindol-1-one derivatives for treating hyperlipemia remedy are disclosed in WO 98/54135.
Syntheses of substituted 2,3-dihydroisoindolinones, other than the compounds of the invention, are reported in, for example, Duckworth et al., J. Chem. Soc., Perkin Trans. 1:815-21, 1996; Kamochi et al., Daiichi Yakka Daigaku Kenkyu Nenpo 20:1-10, 1989; McAlees et al., J. Chem. Soc. Perkin Trans 1, 1:2038-2040, 1977; Tomita et al., J. Chem. Soc. C, 2:183-8, 1969; Do Minh et al., J. Org. Chem., 42:4217-4221, 1977; and O'Sullivan et al., J. Chem. Soc. Chem. Commun., 17:1165-1166, 1984.
Various nucleoside peptides and amide derivatives are shown in, for example, Kawana et al., J. Org. Chem., 37:288-91 (1972); U.S. Pat. Nos: 3,864,483; 3,914,414; 3,914,415; 3,966,917; 4,029,884; and in German patents DE 2417465 and DE 2213180.